AD and Parkinson's disease (PD) are the most frequent progressive neurodegenerative diseases affecting millions of people in the world. Because a significant percentage of patients share common clinical and pathological symptoms from both entities, this seems to indicate the existence of a common pathological mechanism.
Oxidative stress is known to be involved in many diseases, including atherosclerosis, Parkinson's disease and AD, and may be also important in ageing.
Reactive oxygen species (ROS), such as oxygen radical superoxide (O2−) or hydrogen peroxide (H2O2), are produced during normal metabolic processes and perform several useful functions (Reactive oxygen species and the central nervous system, Halliwell B., J. Neurochem.; 1992, 59 859: 1609-1623). Cells are provided with several mechanisms to control levels of these oxidative agents, for instance, superoxide dismutase (SOD), glutathione or vitamin E. In normal physiological conditions, a balance between ROS and these anti-oxidative mechanisms exists. An excessive production of ROS and a loss of efficiency of the anti-oxidative defences can lead to cellular oxidative stress and thus to pathological conditions in cells and provoke tissue damage. This event seems to occur more dramatically in neurons, because of their high rate of metabolic activity, and thus seems to be related to a series of degenerative processes, diseases and syndromes, for example, AD, PD, amyotrophic lateral sclerosis (ALS) and schizophrenia (Glutathione, oxidative stress and neurodegeneration, Schulz et al., Eur. J. Biochem.; 2000, 267, 4904-4911). Also other diseases or pathological conditions have been related to oxidative stress, such as Huntington's Disease (Oxidative damage in Huntington's disease, Segovia J. and Pérez-Severiano F, Methods Mol. Biol.; 2004; 207: 321-334), brain injuries, such as stroke and ischemia, (Oxidative Stress in the Context of Acute Cerebrovascular Stroke, El Kossi et al., Stroke; 2000; 31: 1889-1892), diabetes (Oxidative stress as a therapeutic target in diabetes: revisiting the controversy, Wiernsperger N F, Diabetes Metab.; 2003; 29, 579-85), multiple sclerosis (The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy, Gilgun-Sherki Y. et al., J. Neurol.; 2004; 251 (3): 261-8), epilepsy (Oxidative injury in epilepsy: potential for antioxidant therapy?, Costello D. J. and Delanty N., Expert. Rev. Neurother.; 2004; 4(3):541-553), atherosclerosis (The oxidative stress hypothesis of atherogenesis, luliano L., Lipids; 2001; 36 suppl: S41-44), Friedreich's Ataxia (Oxidative stress mitochondrial dysfuntion and cellular stress response in Friedreich's ataxia, Calabrese et al., J. Neurol. Sci.;2005) and heart failure (Oxygen, oxidative stress, hypoxia and heart failure, Giordano F. J., J. Clinic. Invest.; 2005; 115 (3): 500-508). Treatments that lead to an enhancement of the anti-oxidative mechanisms may slow down the progression of some of the mentioned diseases.
Another type of cellular stress is the endoplasmic reticulum (ER) stress. The ER is an intracellular organelle represented by an extensive network formed by cisternae and microtubules and which extends from the nuclear envelope to the cell surface in all eukaryotic cells. ER plays several vital functions: the rough ER is the place for protein synthesis and postranslational changes for the correct folding of proteins, ER is the common transport route to deliver proteins to their proper destination within the cell and it is also a Ca2+ reservoir. Disturbances in the function of ER lead to accumulation of unfolded proteins within the ER, inducing a condition generally referred to as ER stress. These disturbances can be caused not only by biochemical imbalance but also by disturbance in the ER Ca2+ homeostasis. Some studies (Glycogen synthase kinase 3β (GSK3β) mediates 6-hydroxydopamine-induced neuronal death, Chen et al., FASEB J. 2004;18(10):1162-4) demonstrate that ER stress activates the enzyme glycogen synthase kinase 3β, an enzyme involved in the neurodegenerative process occurred in patients with AD.
The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) is formed endogenously in patients suffering from Parkinson's disease. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. 6-hydroxydopamine (6-OHDA) models are used to produce a broad spectrum of neurochemical and behavioural deficits characterising DA degeneration in humans, specially for PD (e.g. Glinka Y et al, “Mechanism of 6-hydroxydopamine neurotoxicity”, J Neural Transm Suppl. 1997;50:55-66; Willis G L et al, “The implementation of acute versus chronic animal models for treatment discovery in Parkinson's disease” Rev Neurosci. 2004;15(1):75-87).
A common sign of neurodegenerative diseases is the accumulation and deposits of misfolded proteins which affect several signalling pathways which lead finally to neuronal death. Some authors (ER stress and neurodegenerative diseases, Lindholm et al., Cell Death and Differentiation; 2006; 13: 385-392) consider that ER stress is related to several neurodegenerative diseases such as, PD, AD, ALS, and transmissible spongiform encephalopaties (TSEs).
In view of the above, an interesting approach for developing new pharmaceutical compounds for treating neurodegenerative diseases may be designing compounds which inhibit cellular oxidative stress.
Amyloid beta (Aβ) is a peptide that is the main constituent of amyloid plaques in the brains of AD patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy.
Aβ is formed after sequential cleavage of the amyloid precursor protein (APP) by the β- and y-secretases. Either Aβ42 or Aβ40 are produced depending on where the cleavage occurs. APP is a transmembrane glycoprotein. Autosomal-dominant mutations in APP cause hereditary early-onset AD, likely as a result of altered proteolytic processing. Increases in total Aβ levels have been implicated in the pathogenesis of both familial and sporadic AD [The American Journal of Pathology; Lue, L; 155(3):853-662 (1999)].
According to the “amyloid hypothesis”, accepted by the majority of researchers, the plaques are responsible for the pathology of AD. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.
Thus, the development of inhibitors of amyloid beta secretion are a current strategy to find treatments for diseases in which amyloidosis is involved, such as AD, PD, Huntington's disease, TSEs, Prion diseases, Creutzfeldt-Jakob disease and Bovine spongiform encephalopathy.
On the other hand, iron chelators are used to treat some kinds of haematological diseases, such as thalassaemia, anaemia, aplastic anaemia, myelodysplastic syndrome, diabetes, Diamond-Blackfan anaemia, sickle cell disease, hematologic disorders which require regular red cell transfusions, iron-induced cardiac dysfunction, and iron-induced heart failure.
Metals such as iron are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes reactions that produce reactive radicals and can produce reactive oxygen species. The most important reactions are probably Fenton's reaction and the Haber-Weiss reaction, in which hydroxyl radical is produced from reduced iron and hydrogen peroxide. The hydroxyl radical then can lead to modifications of amino acids (e.g. meta-tyrosine and ortho-tyrosine formation from phenylalanine), carbohydrates, initiate lipid peroxidation, and oxidize nucleobases. Most enzymes that produce reactive oxygen species contain one of these metals. The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. Therefore, it is desirable that chelating ligands for the treatment of conditions according to the invention, show a preference towards Fe(II) rather than Fe(III).
Iron chelators deferoxamine and deferiprone, have been used in humans since the 1970s and the late 1980s, respectively, and lately a new drug, deferasirox has been used in humans. Deferoxamine has proven efficient in thalassemia major, sickle cell disease and other hematologic disorders for which hematologic disorders, but can only be administered subcutaneously [Blood; Neufeld, E. L., 107(9): 3436-3441 (2006)]. Deferasirox, approved in the US for chronic iron overload due to blood transfusions, has shown moderate to good success [Hematology; Cohen, A. R., 42-47 (2006)]. Combination therapy with deferiprone and deferoxamine is also being used.
However, side effects have been associated with the use of these drugs; deferiprone often causes gastrointestinal symptoms, erosive arthritis, neutropenia and in some cases agranulocytosis; deferiprone therapy requires weekly complete blood count and ancillary supplies for infusion, so close monitoring is required; deferoxamine presents gastrointestinal symptoms and joint pain and deferasirox is costly. Therefore there still remains a need for additional therapeutic iron chelators for use in these hematological diseases, produced and used with low cost and reduced side effects.
It is well known that phenanthroline derivatives exhibit good iron chelating properties. Some phenanthroline derivatives are shown in patent PL76345. It would be highly recommended to find new phenanthroline derivatives which can show improved properties in chelating iron metal in order to provide an enhanced capability for treating the haematological mentioned diseases.